Major depression is a common, severe, chronic and often life-threatening illness. Although there are many effective treatments for depression, existing therapies have a lag of onset of action of several weeks possibly resulting in considerable morbidity and potentially even mortality by suicide. Thus, there is a clear need to develop novel and improved therapeutics for major depression that have a rapid onset of action. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Clinical data suggests that glutamatergic modulators may have antidepressant effects in humans. We first tested the glutamatergic modulator riluzole (an inhibitor of glutamate release and AMPA modulator) and found it to have antidepressant properties in patients with treatment-resistant major depression and bipolar depression. We recently found that a single intravenous dose of the non-competitive NMDA antagonist ketamine produced a rapid but only transitory antidepressant effect in patients with treatment-resistant major depression. Together, these data suggest that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressant treatments. We propose to expand our previous findings on the efficacy of glutamatergic modulators in patients with severe recurring major depression by testing a specific, new mechanism where by we use riluzole to chronically decrease NMDA throughput in an effort to maintain the acute antidepressant effects brought about by acute NMDA antagonist administration. Patients, ages 18 to 65 years with a diagnosis of recurrent major depressive disorder, will be recruited for this study. This study consists of two study phases designed to examine the maintenance of a rapid antidepressant effect. Study Phase I is open-label treatment with a single intravenous dose of ketamine. Responders to this intervention will be randomized the following morning to double-blind treatment with riluzole or placebo for 4 weeks. The specific aim of this study is to assess the efficacy of riluzole (100-200 mg/day) compared with placebo in preventing symptomatic relapse among patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of an NMDA antagonist (ketamine 0.5 mg/kg over 40 minutes) and are in mild depression. Our primary hypothesis is that subjects with treatment-resistant major depression, who respond to a single dose of an NMDA antagonist when randomized to riluzole 100-200 mg/day, will have a longer time to relapse compared to subjects randomized to placebo.